HucMSC Exosome-Delivered 14-3-3ζ Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration.
Stem Cells
; 34(10): 2485-2500, 2016 10.
Article
em En
| MEDLINE
| ID: mdl-27334574
ABSTRACT
Numerous studies showed that mesenchymal stem cells derived exosome (MSC-Ex) markedly enhanced tissue regeneration, however, the issue of whether MSC-Ex could control stem cells expansion after a regenerative response to prevent tissue from overcrowding and dysplasia remains to be established. Herein, we found that human umbilical cord MSC (hucMSC)-exosomal14-3-3ζ mediated the binding of YAP and p-LATS by forming a complex to promote the phosphorylation of YAP, which orchestrate exosomal Wnt4 signal in cutaneous regeneration. First, we assessed deep second-degree burn rats treated with hucMSC-Ex and discovered that hucMSC-Ex promoting self-regulation of Wnt/ß-catenin signaling at the remodeling phase of cutaneous regeneration. HucMSC-Ex restricted excessive skin cell expansion and collagen deposition at 4 weeks. Under high cell density conditions, hucMSC-Ex inhibited Wnt/ß-catenin signaling through induction of YAP phosphorylation. Second, hucMSC-Ex proteomic analysis revealed that 14-3-3 proteins could be transported by exosome. Using gain- and loss-of-function studies, our results showed that hucMSC-exosomal 14-3-3ζ controlled YAP activities and phosphorylation at Ser127 site, and were required for the binding of YAP and p-LATS. Further studies revealed that 14-3-3ζ recruited YAP and p-LATS to form a complex under high cells density status and 14-3-3ζ other than YAP or p-LATS was the key regulatory molecule of this complex. These findings collectively indicate that hucMSC-Ex functions not only as an "accelerator" of the Wnt/ß-catenin signal to repair damaged skin tissue but also as a "brake" of the signal by modulating YAP to orchestrate controlled cutaneous regeneration. Stem Cells 2016;342485-2500.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Regeneração
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Pele
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Cordão Umbilical
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Proteínas Adaptadoras de Transdução de Sinal
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Proteínas 14-3-3
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Proteínas Wnt
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Exossomos
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Células-Tronco Mesenquimais
Limite:
Humans
Idioma:
En
Revista:
Stem Cells
Ano de publicação:
2016
Tipo de documento:
Article